<p>Fluorescent metal organic frameworks (FMOFs) constructed by encapsulating aggregation-induced emission luminogens (AIEgens) into frameworks have garnered increasing attention due to their ability to overcome the aggregation-caused quenching (ACQ) effect of traditional fluorescent materials such as organic dyes, quantum dots, and up-conversion nanoparticles. However, conventional AIEgens usually contain aromatic groups that may pose potential health risks. Additionally, the quality of bisphosphonates (BPs), first-line treatment drugs in skeletal-related diseases, is critical to assure their effectiveness and safety. In this work, a new nanocomposite, Pt NCs@ZIF-8, was designed by encapsulating platinum nanoclusters (Pt NCs) with aggregation-induced emission (AIE) properties into zeolitic imidazolate framework-8 (ZIF-8) through self-assembly between Zn²⁺ and Pt NCs. Owing to the spatial confinement provided by ZIF-8 and the AIE effect of Pt NCs, the resulting Pt NCs@ZIF-8 nanocomposite presents excellent photostability and anti-photobleaching. Furthermore, the framework of Pt NCs@ZIF-8 collapses in the presence of BP drugs due to the strong coordination interaction between the P = O groups in BPs and the Zn²⁺ in ZIF-8, leading to the release of Pt NCs. This release of Pt NCs causes effective fluorescence quenching of the Pt NCs@ZIF-8 nanocomposite, resulting from the increasing intramolecular motion of surface ligands, glutathione (GSH), on Pt NCs. Therefore, a new Pt NCs@ZIF-8-based nanoprobe has been rationally designed for BP detection. More importantly, our designed Pt NCs@ZIF-8-based nanoprobe also presents excellent discrimination capability toward four structurally similar BPs—Etidronate, Clodronate, Alendronate, and Risedronate, as confirmed by statistical techniques such as principal component analysis (PCA) and hierarchical clustering analysis (HCA). Finally, the proposed Pt NCs@ZIF-8 nanoprobe was successfully applied to quantify the labeled amount percentage of commercially available Sodium Risedronate and Sodium Alendronate tablets, achieving satisfactory limits of detection (LOD) spanning from 1.2 to 8.8&#xa0;µM and excellent recovery ranging from 97.50% to 102.6%. This work not only provides a novel and convenient strategy for detecting and distinguishing BPs but also demonstrates the potential application of metal–organic frameworks encapsulating metal nanoclusters with AIE properties in pharmaceutical quality control.</p> Graphical Abstract <p></p>